Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause of death in trauma patients surviving the initial 72 hour injury period. In fact, MODS is the leading cause of death in ICUs today. Although still somewhat controversial, there is recent evidence that the response to injury and sepsis may differ between males and females, with females being more resistant to the adverse consequences of T/HS than males. Thus, understanding the mechanisms by which trauma-hemorrhagic shock (T/HS) leads to MODS, as well as the role of sex hormones in modulating this response, is of major health importance. This Project will follow up on our results indicating that male, but not female, rats develop T/HS-induced lung injury and endothelial cell activation/injury by testing the following two hypotheses. The first hypothesis is that T/HS-induced lung injury and increased endothelial cell permeability is secondary to gut injury and is mediated by factors exiting the gut via the mesenteric lymphatics but not the portal vein. The second hypothesis is that sex hormones modulate gut and hence distant organ injury in a model of T/HS. To test these hypotheses, we will first investigate the potential mechanisms of why the female gut is more resistant than the male gut to T/HS-induced gut injury and does not produce toxic lymph. Next, we will investigate the role of sex hormones as modulators of resistance and susceptibility to T/HS-induced gut and lung injury. We will investigate the hypothesis that estrogen protects against T/HS-induced gut injury by limiting iNOS induction. Lastly, we will investigate the mechanisms by which T/HS mesenteric lymph, alone or in combination with PMNs, increases vascular permeability and how this is influenced by gonadal hormonal manipulation.